More Recent Comments

Friday, January 04, 2013

Science Magazine Chooses ENCODE Results as One of the Top Ten Breakthroughs in 2012

Science magazine (published by AAAS) was one of the major news sources that fell hook, line and sinker for the ENCODE/Nature publicity campaign last September [Science Writes Eulogy for Junk DNA]. It even published a laudatory three page profile of Ewan Birney, the man responsible for misrepresenting the ENCODE results as evidence that most of our genome is functional [Ewan Birney: Genomics' Big Talker].

I was somewhat apprehensive when I saw that the editors of Science had picked the ENCODE results as one of the top ten breakthroughs [Genomics Beyond Genes]. Would the editors continue to promote the idea that most of the human genome is functional?

The short answer is "yes," as you can see from the summary box below. The person who wrote the article says that "the functional portion of the genome" is 80% of the total. He/she emphasizes this in the text ...

ENCODE researchers took an intensive look not just at genes but at all of the DNA in between. Their results drive home that much of the genome that at one time was dismissed as "junk DNA" actually seems to play an essential role, often by helping to turn genes on or off. They pinpointed hundreds of thousands of landing spots for proteins that influence gene activity, many thousands of stretches of DNA that code for different types of RNA, and lots of places where chemical modifications serve to silence stretches of our chromosomes, concluding that 80% of the genome was biochemically active.

This is, as we now know, very misleading. Just because DNA binding proteins are found on DNA does not mean that the binding site has a function. Just because a region of DNA is transcribed on occasion does not mean that the RNA is functional. You do not overthrow 40 years of evidence that most of our genome is junk on the basis of spurious binding sites and aberrant transcription.

Besides, we already knew about all these results years ago so the September papers do not count as a real "breakthrough" by any stretch of the imagination. But Science justifies the "breakthrough" status by pointing out that major newspapers were fooled ...

When these papers were published in September, the media went wild. ENCODE was hailed in The New York Times as a "stunning resource" and "a major medical and scientific breakthrough" with enormous and immediate implications for human health. The Guardian called it "the most significant shift in scientists' understanding of the way our DNA operates since the sequencing of the human genome."

This is a cop-out. Science is published by a scientific organization and we expect a more serious appraisal than what you might see in newspapers. What do the editors of Science think? Do they also believe that the ENCODE results represent a "significant shift in scientists' understanding of the way our DNA operates"? 'Cause if they do, they are as wrong as the journalists who wrote for The Guardian.

In fairness, someone at Science decided that it would be a good idea to mention the controversy, so they added

But several scientists in the blogosphere called the coverage overhyped and blamed the journals and ENCODE leaders for overplaying the significance of the results. For example, ENCODE reported that 76% of DNA is transcribed to RNA, most of which does not go on to help make proteins. Various RNAs home in on different cell compartments, as if they have fixed addresses where they operate, suggesting that they play a role in the cell. Critics argue, however, that it was already known that a lot of RNA was made, and that many of these RNAs may be spurious genome products that serve no purpose. Likewise, one ENCODE researcher found 3.9 million regions across 349 types of cells where proteins called transcription factors bind to the genome—but again, it's unclear how much of that binding is functional.

I suppose we have to give them credit for recognizing that there's a problem but it's clear that the person who wrote the article doesn't really believe the critics otherwise he/she would never have led off with this statement ...

Their results drive home that much of the genome that at one time was dismissed as "junk DNA" actually seems to play an essential role, often by helping to turn genes on or off.

All in all, this is just another example of bad science journalism. Science magazine is shirking its responsibility as a leading science magazine. Either the ENCODE publicists are correct or the scientists in the blogosphere are correct. They can't both be right. The editors of Science owe it to their readers to get to the bottom of this controversy.

Is it, or is it not, true that most of the human genome is functional? It still looks to me like the editors have chosen the wrong side of the controversy.

I have never claimed that "peer-review" ensures accuracy. I subscribe to the idea that most of what's published in the scientific literature is wrong and will be completely forgotten a few months after publication.

It's creationists who have a problem with peer review. They categorically reject all those thousands of peer-reviewed papers supporting evolution but, when one paper raises doubts about a particular aspect of evolution, the creationists fall all over themselves praising it as genuine peer-reviewed science.

And whenever a creationist gets published in the peer-reviewed literature, they shout it from the rooftops. They want to have their cake and eat it too.

I can't tell if it's just because I'm a very new and naive scientist, but I feel like I'm quickly losing trust in Science and Nature - like they've become so obsessed with publishing the big stories that they've tossed basic scientific rigor out the window. Surely, if this is how they are now, they haven't always been so bad?

And I wish I was just talking about the few major media-frenzy items, like ENCODE and arsenic bacteria. But I've seen a few other rotten apples coming out that didn't get the same press coverage, but were almost as bad at doing what they set out to do.

Is it, or is it not, true that most of the human genome is functional?

No. The question is what is the definition of "function" that is relevant to the Junk DNA hypothesis.

Transcription to RNA is not "function" by any definition relevant to the Junk DNA hypothesis.

Chemical modification and binding proteins MAY be relevant the Junk DNA hypothesis, but in an reverse sense from that meant by Junk DNA deniers. That is, chemical modification and binding proteins may either be random noise applied to random sequence matches, or they may have the "function" of silencing transcription of old transposons or viral DNA. That is also a "function", but not "function" in the sense of disproving Junk DNA.

It all depends on your definition of functional; one man's 'spurious binding sites' are another man's 'sites of protein sequestration'. Just because it does not have an obvious function at the moment does not mean it will never have a function as our knowledge of biological systems grows.

Your question is based on a false premise, and I think you calculated it that way.

Your question is based on the false premise that Moran thinks his definition of "function" is superior to Science's definition. He claimed no such thing. In biochemistry, "function" can have many, many, many definitions and each can be relevant in different contexts.

However, Science has claimed that ENCODE "functional" assays (actually assays for biochemical activity) disproved the Junk DNA hypothesis. If one is referencing the Junk DNA hypothesis, one must use the definition of "function" relevant to the Junk DNA hypothesis.

The definition of "function" invented wholecloth by Ewan Birney, function = biochemical activity, may be relevant in some contexts, but it is remotely distant from the definition relevant to the Junk DNA hypothesis.

Even way back in 1980, the scientists who coined the term "Junk DNA" explicitly said that much Junk DNA can be transcribed into RNA. So if one claims that RNA transcription could in principle disprove the Junk DNA hypothesis, they're either lying or very, very ignorant.

It is profoundly, profoundly dishonest to claim that ENCODE biochemical assays were capable of disproving the Junk DNA hypothesis, by engaging in equivocation-- switching between two definitions of a single word.

CuriousOnlooker, please be careful about asking questions based on false premises. If you do it again, I will start to get pissed off.

It's not Science's definition, but ENCODE's. This is not a matter of superiority but of meaning. That repetitive DNA could be transcribed accidentally once in a while, and thus be matched to many more regions than were actually transcribed, is not function proper, but transcriptional accident. That DNA can be remodelled, recombined, and such, because of some repetitive DNA regions is not function proper either, but shit that happens because of the nature of the recombination process itself. Et cetera.

If I may: It's not really a question of which definition if "superior", but rather of whether the definition is being used consistently. If you use a definition of "functional" that would include most junk DNA, then go on to say since 80% of the genome is "functional" this means that 80% of the genome is not junk, you are obviously being inconsistent.

Why do you think your definition of "functional" is superior to Science's definition?

I think that "function" has to mean a biologically relevant activity that affects the survival of the organism.

Let me give you an example. Some protein-encoding genes become inactivated by acquiring a mutation that causes premature termination of protein synthesis. This is a very well-known phenomenon in bacterial and 'phage genetics and it's also one of the mechanisms giving rise to pseudogenes in our genome.

Those pseudogenes can still have active promoters and they are still transcribed to produce mRNA. The promoter region still binds various transcription factors.

The gene is nonfunctional by my definition because it has lost its biological activity. It is now junk DNA.

However, this region of the genome is still "functional" by the definition used by ENCODE publicists and by Science editors because it is transcribed and because proteins still bind. I don't think such a re-definition of "functional" is particularly helpful in understanding how our genome works.

As others have pointed out, the re-definition of "functional" includes known examples of junk DNA so it really doesn't make any contribution to the debate over the amount of junk in our genome.

Moran: "I think that "function" has to mean a biologically relevant activity that affects the survival of the organism."

I'm surprised you think fitness is important in a definition of functional genomics and I'm not sure how it's relevant. I think the way we understand function is in the relationship of genome to phenotype.

Diogenes: Haha! You really think I give a furry rodent's posterior about you getting pissed off? I don't because:

a. This is not your blog.b. Whether you see it that way or not, I did feel that the definition of DNA having a protein-coding function was somehow seen as "superior". It's not my fault that you are incapable of comprehending a question as anything other than an ad hominem attack.

And by the way, it's perfectly fine to believe that one definition in science can be superior to others. For instance, the definition of complex life as evolved from simpler organisms is superior to the definition of life as being created by a supernatural being.

Whether you see it that way or not, I did feel that the definition of DNA having a protein-coding function was somehow seen as "superior".

Jesus, we're back to the goddamn "non-coding DNA = junk DNA" bullshit. Scientists have fucking known since the 1960's that non-coding DNA can have a function, by the definition of function relevant to Junk DNA.

How many times do I have to list all the goddamn scientists who won goddamn Nobel Prizes from the goddamn Swedish committee for finding functions in non-coding DNA? How many times do I have to copy and paste that fucking list?

The structure of tRNA was known by 1964, crystal structure solved in 1974. tRNA is made from non-coding RNA.

The ribosome was known to be largely nucleic acid in the 1950's, general molecular structure known since the early 1970s, by the 1980's it was known the ribosome was a ribozyme-- based on functions residing in non-coding DNA.

Why do you think they got those Nobel Prizes? Because everybody has known since the 1960's that non-coding DNA can have a function, by the definition of function relevant to Junk DNA.

And by the way, it's perfectly fine to believe that one definition in science can be superior to others. For instance, the definition of complex life as evolved from simpler organisms is superior to the definition of life as being created by a supernatural being.

Neither of these is a definition. A definition explains the meaning of a term, not the origin of natural phenomena.

Laurence A. Moran

Larry Moran is a Professor Emeritus in the Department of Biochemistry at the University of Toronto. You can contact him by looking up his email address on the University of Toronto website.

Sandwalk

The Sandwalk is the path behind the home of Charles Darwin where he used to walk every day, thinking about science. You can see the path in the woods in the upper left-hand corner of this image.

Disclaimer

Some readers of this blog may be under the impression that my personal opinions represent the official position of Canada, the Province of Ontario, the City of Toronto, the University of Toronto, the Faculty of Medicine, or the Department of Biochemistry. All of these institutions, plus every single one of my colleagues, students, friends, and relatives, want you to know that I do not speak for them. You should also know that they don't speak for me.

Subscribe to Sandwalk

Quotations

The old argument of design in nature, as given by Paley, which formerly seemed to me to be so conclusive, fails, now that the law of natural selection has been discovered. We can no longer argue that, for instance, the beautiful hinge of a bivalve shell must have been made by an intelligent being, like the hinge of a door by man. There seems to be no more design in the variability of organic beings and in the action of natural selection, than in the course which the wind blows.Charles Darwin (c1880)Although I am fully convinced of the truth of the views given in this volume, I by no means expect to convince experienced naturalists whose minds are stocked with a multitude of facts all viewed, during a long course of years, from a point of view directly opposite to mine. It is so easy to hide our ignorance under such expressions as "plan of creation," "unity of design," etc., and to think that we give an explanation when we only restate a fact. Any one whose disposition leads him to attach more weight to unexplained difficulties than to the explanation of a certain number of facts will certainly reject the theory.

Charles Darwin (1859)Science reveals where religion conceals. Where religion purports to explain, it actually resorts to tautology. To assert that "God did it" is no more than an admission of ignorance dressed deceitfully as an explanation...

Quotations

The world is not inhabited exclusively by fools, and when a subject arouses intense interest, as this one has, something other than semantics is usually at stake.
Stephen Jay Gould (1982)
I have championed contingency, and will continue to do so, because its large realm and legitimate claims have been so poorly attended by evolutionary scientists who cannot discern the beat of this different drummer while their brains and ears remain tuned to only the sounds of general theory.
Stephen Jay Gould (2002) p.1339
The essence of Darwinism lies in its claim that natural selection creates the fit. Variation is ubiquitous and random in direction. It supplies raw material only. Natural selection directs the course of evolutionary change.
Stephen Jay Gould (1977)
Rudyard Kipling asked how the leopard got its spots, the rhino its wrinkled skin. He called his answers "just-so stories." When evolutionists try to explain form and behavior, they also tell just-so stories—and the agent is natural selection. Virtuosity in invention replaces testability as the criterion for acceptance.
Stephen Jay Gould (1980)
Since 'change of gene frequencies in populations' is the 'official' definition of evolution, randomness has transgressed Darwin's border and asserted itself as an agent of evolutionary change.
Stephen Jay Gould (1983) p.335
The first commandment for all versions of NOMA might be summarized by stating: "Thou shalt not mix the magisteria by claiming that God directly ordains important events in the history of nature by special interference knowable only through revelation and not accessible to science." In common parlance, we refer to such special interference as "miracle"—operationally defined as a unique and temporary suspension of natural law to reorder the facts of nature by divine fiat.
Stephen Jay Gould (1999) p.84

Quotations

My own view is that conclusions about the evolution of human behavior should be based on research at least as rigorous as that used in studying nonhuman animals. And if you read the animal behavior journals, you'll see that this requirement sets the bar pretty high, so that many assertions about evolutionary psychology sink without a trace.

Jerry Coyne
Why Evolution Is TrueI once made the remark that two things disappeared in 1990: one was communism, the other was biochemistry and that only one of them should be allowed to come back.

Sydney Brenner
TIBS Dec. 2000
It is naïve to think that if a species' environment changes the species must adapt or else become extinct.... Just as a changed environment need not set in motion selection for new adaptations, new adaptations may evolve in an unchanging environment if new mutations arise that are superior to any pre-existing variations

Douglas Futuyma
One of the most frightening things in the Western world, and in this country in particular, is the number of people who believe in things that are scientifically false. If someone tells me that the earth is less than 10,000 years old, in my opinion he should see a psychiatrist.

Francis Crick
There will be no difficulty in computers being adapted to biology. There will be luddites. But they will be buried.

Sydney Brenner
An atheist before Darwin could have said, following Hume: 'I have no explanation for complex biological design. All I know is that God isn't a good explanation, so we must wait and hope that somebody comes up with a better one.' I can't help feeling that such a position, though logically sound, would have left one feeling pretty unsatisfied, and that although atheism might have been logically tenable before Darwin, Darwin made it possible to be an intellectually fulfilled atheist

Richard Dawkins
Another curious aspect of the theory of evolution is that everybody thinks he understand it. I mean philosophers, social scientists, and so on. While in fact very few people understand it, actually as it stands, even as it stood when Darwin expressed it, and even less as we now may be able to understand it in biology.

Jacques Monod
The false view of evolution as a process of global optimizing has been applied literally by engineers who, taken in by a mistaken metaphor, have attempted to find globally optimal solutions to design problems by writing programs that model evolution by natural selection.